P2-168: Acetylcholine slows neurodegeneration in a tauopathy model mouse

Abstract

Background: We have reported that neuro-inflammatory reaction is an early and important event leading tau pathology and neuronal loss in neurodegenerative tauopathies by analyzing a FTDP-17 model mouse with P301S tau mutation (line PS19) (Yoshiyama et. al., 2007). Recent studies indicate that acetylcholine (ACh), which is an important neurotransmitter linking cognitive functions and is profoundly depleted in Alzheimer’s disease (AD), may have an anti-inflammatory action in the brain. Additionally, there is evidence that acetylcholinesterase inhibitors (AChEIs) may show disease progression and hippocampal atrophy and may have disease-modifying effects. Methods: To investigate the pathological and therapeutic roles of ACh in tauopathies, we therefore administrate donepezil (DZ), an AChEI, and trihexyphenidyl (TP), an anti-cholinergic agent, to PS19 mice for eight months, and then pathologically and biochemically analyzed them at ten months of age. Results: Histochemical analysis showed that DZ ameliorated synaptic loss, neuronal loss, and tau pathology, but TP deteriorated all of them, compared with PS19 mice at same age. Microglia was dramatically activated in the brain form TP-administrated PS19, but microglial activation was suppressed in the brain form DZ-administrated PS19. Tau insolubility analysis by sequential extraction of brain samples with buffers of increasing extraction strength demonstrated increased tau insolubility in the brain from TP-administrated PS19 mice. To prove anti-inflammatory action of AChEI, we peritoneally injected LPS to PS19 mice with or without administration of DZ for one month. The IL1 and cox-2 expressions in the spleen were suppressed by DZ, indicating that DZ may prevent inflammation systemically not just in the brain. Conclusions: Our data indicated that ACh didn’t act just as a cognition-linking neurotransmitter, but may suppress the pathological mechanism of tauopathies by the anti-inflammatory action. Since numerous experiments have also shown that -amyloid disrupts ACh synthesis, ACh depletion might lead or enhance tau pathology by activated neuro-inflammation in AD.